2. Academic Validation
  3. Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy

Inhibition of IRE1 RNase activity modulates the tumor cell secretome and enhances response to chemotherapy

  • Nat Commun. 2018 Aug 15;9(1):3267. doi: 10.1038/s41467-018-05763-8.
Susan E Logue 1 2,  Eoghan P McGrath 1 2,  Patricia Cleary 1 2,  Stephanie Greene 3,  Katarzyna Mnich 1 2,  Aitor Almanza 1 2,  Eric Chevet 4 5,  Róisín M Dwyer 6,  Anup Oommen 2,  Patrick Legembre 4 5,  Florence Godey 4 5,  Emma C Madden 1 2,  Brian Leuzzi 1 2,  Joanna Obacz 4 5,  Qingping Zeng 7,  John B Patterson 3,  Richard Jäger 8,  Adrienne M Gorman 1 2,  Afshin Samali 9 10
Affiliations

Affiliations

  • 1 Apoptosis Research Centre, National University of Ireland Galway, University Road, Galway, H91 TK33, Ireland.
  • 2 School of Natural Sciences, National University of Ireland Galway, University Road, Galway, H91 TK33, Ireland.
  • 3 Fosun Orinove PharmaTech Inc., 3537 Old Conejo Road, Suite 104, Newbury Park, CA, 91320, USA.
  • 4 Inserm U1242, Chemistry Oncogenesis Stress Signaling, Université de Rennes 1, Avenue de la Bataille Flandres Dunkerque, 35042, Rennes, France.
  • 5 Centre de Lutte Contre le Cancer Eugène Marquis, Avenue de la Bataille Flandres Dunkerque, 35042, Rennes, France.
  • 6 LAM 2015, Discipline of Surgery, Lambe Institute for Translational Research, National University of Ireland Galway, Costello Road, Galway, H91 V4AY, Ireland.
  • 7 Fosun Orinove PharmaTech Inc., Suite 211, Building A4, 218 Xinghu St., Suzhou Industrial Park, Jiangsu, 215123, China.
  • 8 Hochschule Bonn-Rhein-Sieg, University of Applied Sciences, Department of Natural Sciences, von-Liebig-Straße 20, 53359, Rheinbach, Germany.
  • 9 Apoptosis Research Centre, National University of Ireland Galway, University Road, Galway, H91 TK33, Ireland. afshin.samali@nuigalway.ie.
  • 10 School of Natural Sciences, National University of Ireland Galway, University Road, Galway, H91 TK33, Ireland. afshin.samali@nuigalway.ie.
PMID: 30111846 DOI: 10.1038/s41467-018-05763-8
Abstract

Triple-negative breast Cancer (TNBC) lacks targeted therapies and has a worse prognosis than Other breast Cancer subtypes, underscoring an urgent need for new therapeutic targets and strategies. IRE1 is an endoplasmic reticulum (ER) stress sensor, whose activation is predominantly linked to the resolution of ER stress and, in the case of severe stress, to cell death. Here we demonstrate that constitutive IRE1 RNase activity contributes to basal production of pro-tumorigenic factors IL-6, IL-8, CXCL1, GM-CSF, and TGFβ2 in TNBC cells. We further show that the chemotherapeutic drug, paclitaxel, enhances IRE1 RNase activity and this contributes to paclitaxel-mediated expansion of tumor-initiating cells. In a xenograft mouse model of TNBC, inhibition of IRE1 RNase activity increases paclitaxel-mediated tumor suppression and delays tumor relapse post therapy. We therefore conclude that inclusion of IRE1 RNase inhibition in therapeutic strategies can enhance the effectiveness of current chemotherapeutics.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-104040
    99.95%, IRE1α RNase Inhibitor